Dendritic Integration Dysfunction in Neurodevelopmental Disorders
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Models and Mechanisms: Review
Dev Neurosci 2021;43:201–221 Received: January 19, 2021
Accepted: April 13, 2021
DOI: 10.1159/000516657 Published online: June 17, 2021
Dendritic Integration Dysfunction in
Neurodevelopmental Disorders
Andrew D. Nelson Kevin J. Bender
Department of Neurology, University of California, San Francisco, San Francisco, CA, USA
Keywords tors, regulate the expression or scaffolding of dendritic ion
Neurodevelopmental disorder · Epilepsy · Autism spectrum channels, receptors, and synaptic proteins. Therefore, we
disorder · Dendrite · Channelopathy discuss how dysfunction of subsets of NDD-associated genes
in dendrites leads to defects in dendritic integration and ex-
citability and may be one core phenotype in ASD and ID.
Abstract © 2021 The Author(s).
Neurodevelopmental disorders (NDDs) that affect cognition, Published by S. Karger AG, Basel
social interaction, and learning, including autism spectrum
disorder (ASD) and intellectual disability (ID), have a strong Introduction
genetic component. Our current understanding of risk genes
highlights two main groups of dysfunction: those in genes Autism spectrum disorder (ASD) and intellectual dis-
that act as chromatin modifiers and those in genes that en- ability (ID) are two of the most common neurodevelop-
code for proteins localized at or near synapses. Understand- mental disorders (NDDs), with an incidence of 1 in 54
ing how dysfunction in these genes contributes to pheno- births [1]. These NDDs have a strong genetic component,
types observed in ASD and ID remains a major question in and substantial progress has been made to uncover the
neuroscience. In this review, we highlight emerging evi- genetic architecture that contributes to impaired neuro-
dence suggesting that dysfunction in dendrites – regions of biology and behavioral phenotypes. A key challenge for
neurons that receive synaptic input – may be key to under- the field has been to translate these findings into an un-
standing features of neuronal processing affected in these derstanding of pathophysiology at the cellular and circuit
disorders. Dendritic integration plays a fundamental role in level, with the goal of identifying key points of conver-
sensory processing, cognition, and conscious perception, gence across ASD/ID genes within the brain. Many excel-
processes hypothesized to be impaired in NDDs. Many high- lent commentaries and reviews have advanced major
confidence ASD genes function within dendrites where they themes of convergence in these disorders, including defi-
control synaptic integration and dendritic excitability. Fur- cits in synaptic balance, connectivity, predictive process-
ther, increasing evidence demonstrates that several ASD/ID ing, and in “top-down bottom-up” processing of stimuli
genes, including chromatin modifiers and transcription fac- relative to internal brain states [2–9]. Mechanistically,
karger@karger.com © 2021 The Author(s). Correspondence to:
www.karger.com/dne Published by S. Karger AG, Basel Kevin J. Bender, kevin.bender @ ucsf.edu
This is an Open Access article licensed under the Creative Commons
Attribution-NonCommercial-4.0 International License (CC BY-NC)
(http://www.karger.com/Services/OpenAccessLicense), applicable to
the online version of the article only. Usage and distribution for com-
mercial purposes requires written permission.considerable attention has been paid to how NDD-asso- ceive input from neighboring pyramidal cells as well as
ciated genes affect synapse function. Here, we discuss partners from similar cortical regions in the contralateral
how extending beyond synapses to the dendrites in which hemisphere [26–28]. These pyramidal cells also have one
they reside – and understanding how alterations in den- or more apical dendrites that arborize extensively in layer
dritic structure, excitability, and integration, either driv- 1, a layer relatively devoid of somata but rich in neurites.
en by or driving synaptic alterations – can help link theo- Synapses made in layer 1 onto the apical tufts of pyrami-
ries of ASD/ID to cellular mechanisms affected in these dal cells largely arise from long-range sources, including
disorders. other regions of cortex, thalamocortical recurrent loops,
In this review, we focus primarily on neocortical re- and sources of neuromodulatory transmitters [29–31].
gions and neuronal processing within pyramidal cell den- Thus, neocortex circuitry is organized to allow associative
drites. As a site for higher order sensory processing, plan- processing by making comparisons between local inputs
ning, and cognition, the neocortex has long been consid- and long-range inputs, reflecting circuit states in other
ered a key site for ASD/ID pathophysiology. Neocortical brain regions (Fig. 1a). Within this framework, pyramidal
volume expands considerably across mammalian evolu- cells play a central role, as their dendrites can sample both
tion, with parallel expansion in circuit complexity [10]. local sources in basal dendrites and long-range sources in
The neocortex is a multilayered structure, with each layer their apical dendrites. In 1999, Larkum and colleagues
containing specific cell classes that have unique morphol- provided the first empirical observations that dendrites of
ogies and synaptic connectivity. These synapses can be layer 5 pyramidal cells can perform such computations,
local, within regions that process similar information, or allowing for coincidence detection between basal and api-
long-range, spanning regions to provide associative, con- cal regions [32]. In these experiments, they observed that
textual information to different regions of cortex. Pyra- pairing action potentials (APs) in the axon initial segment
midal cells, which have dendrites spanning multiple lay- (AIS) with excitatory synaptic input into the apical tuft
ers, are uniquely positioned to integrate both local and can lead to supralinear voltage responses in the dendrite
long-range inputs, thereby acting as cellular structures that, in turn, result in enhanced neuronal output in the
that integrate disparate streams of input to help guide be- form of a high-frequency AP burst (Fig. 1b). This mecha-
havior. In particular, layer 5 pyramidal cells, which have nism occurred only within a narrow temporal window,
dendrites that span all layers, have emerged as an impor- thereby serving as a coincidence detector for near-simul-
tant cell class for sensory discrimination and conscious taneous activation of these two compartments. Further-
perception [11]. Interestingly, coexpression network more, they showed that dendritic supralinearities can be
analysis from whole-exome sequencing data revealed that vetoed by local inhibitory inputs. Remarkably, as dis-
multiple high-confidence ASD genes are highly expressed cussed below, the cellular mechanisms that support each
in layers 5 and 6 glutamatergic projection neurons, high- of these features have been shown to be disrupted in
lighting these neurons as a central locus at which ASD ASD/ID.
risk genes converge [12–16]. Thus, a better understand- This landmark discovery brought forth more than a
ing of how these neurons process information may shed decade of research on cellular mechanisms present in
light on the neurobiological mechanisms disrupted in dendrites that allow for “feature detection” in synaptic
NDDs. We note, however, that pyramidal cells are just inputs. These features, which have been described in
one of many cell classes that are important for ASD/ID detail in excellent review articles [33–35], include (1)
etiology and that many of the themes discussed here are the generation of “dendritic spikes,” which occur when
broadly applicable across brain regions, including stria- synaptic input paired with or without AP-mediated de-
tum, cerebellum, and other subcortical regions [17–25]. polarization results in regenerative supralinearities
within dendritic compartments, independent of APs
initiated in the AIS (Fig. 1b, c) [36]; (2) detection of co-
Main Text incident synaptic input onto single dendritic branches,
independent of the location of this branch within the
Current Understanding of Pyramidal Cell Dendritic overall dendritic arbor; (3) the directionality of activa-
Function tion of such inputs on single branches (i.e., in a cascade
Neocortical pyramidal cells in layers 2, 3, and 5 have either toward or away from the soma; Fig. 1d) [37]; and
characteristic dendritic morphologies. Basal dendrites in (4) XOR (eXclusively OR) computations, where den-
proximity to the soma are studded with spines that re- drites are capable of signaling the occurrence of one of
202 Dev Neurosci 2021;43:201–221 Nelson/Bender
DOI: 10.1159/000516657Coincidence detection Apical tuft Dendritic
Long-range of tuft EPSPs and dendritic spike branch spike individual EPSPs
inputs backpropagating AP
axonal APs 9 1
volley of 7 5
4
tuft activity
8
6 2
3
EPSP
+
AP
dendritic spike
(observed)
Local inputs dendritic AP burst arithmetic sum
AP burst tuft spike output (expected)
output
a b c EPSPs d 1 9
Fig. 1. Mechanisms of synaptic integration on layer 5 pyramidal quency AP bursts onto apical tuft dendrites alone can evoke den-
neurons dendrites in neocortex. a Approximation of synaptic in- dritic spikes and subsequent APs from the axon. d Synchronous
puts to neocortical layer 5 pyramidal neurons, which tend to inte- synaptic input on dendritic branches drives individual EPSPs.
grate long-range synaptic inputs onto apical tuft dendritic branch- When combined in a cascade of events from distal to more proxi-
es and local inputs on basal dendrites. b Coincidence detection mal parts of the soma, these EPSPs summate to generate events
between apical dendritic EPSPs and APs from basal regions gener- larger than their arithmetic sum (e.g., dendritic spike). EPSPs, ex-
ates supralinear depolarizations and axonal AP bursts. c High-fre- citatory postsynaptic potentials; APs, action potentials.
two inputs (X or Y), but not both (X and Y), a process sociated with a barrage of APs that, in turn, engages thal-
previously thought to require a multicellular network amocortical loops thought to be critical for neocortical
[38]. These processes often result from coordinated processing [28, 51]. Causal manipulations that block the
synaptic engagement within a small region of dendrite, generation of dendritic spikes, often by engaging inhibi-
which allows synaptic depolarizations to accumulate, tory networks that preferentially target the apical tuft, in-
thereby relieving voltage-dependent magnesium block terfere with perception [52]. Furthermore, these dendrit-
of N-methyl-D-aspartate (NMDA) receptors [39]. This, ic tuft spikes appear to be critical for conscious percep-
in itself, promotes further local depolarization, but tion, as they are some of the first subcellular events to be
NMDA receptor activation is often not the sole mecha- disrupted by anesthetics [53]. Together, these data iden-
nism underlying dendritic supralinarities. As these tify a major role for pyramidal cell dendrites in higher
dendrites depolarize, several voltage-gated channels order neocortical function. Furthermore, they highlight
can be recruited, including multiple sodium (NaV) and the complexity and convergence of multiple processes
calcium (CaV) channel proteoforms [40–42]. In addi- that regulate dendritic excitability, which includes intrin-
tion, other channels can be inactivated, including po- sic mechanisms within the dendrite, excitatory and in-
tassium (KV) and hyperpolarization-activated cyclic hibitory synaptic input to the apical tuft, and, as discussed
nucleotide-gated (HCN) channels [43–45]. Thus, any further below, neuromodulatory pathways that alter sig-
disruption in dendritically localized channels or recep- nal processing in such regions.
tors that contribute to dendritic excitability – whether Disruption in how dendrites process sensory input
localized to the synapse itself or instead in the dendrit- may fit into a mechanistic theory of ASD that proposes
ic shaft – could interfere with pyramidal cell processing an altered balance in “top-down bottom-up” processing,
and synaptic plasticity associated with dendritic supra- with a bias toward bottom-up processing in ASD/ID. In
linearities [46, 47]. terms of cognitive processes, this can be thought of as an
Dendritic supralinearities are increasingly being rec- inability to attend to specific stimuli (in the case of sen-
ognized as critical for active perception and decision- sory processing), or specific streams of thought (in the
makingin vivo. Using calcium imaging approaches and case of associative, or internal state processing), due to a
direct electrophysiological recording from dendrites, the loss of “top-down” attentional control. Rather, “bottom-
apical dendritic tuft of both layer 2/3 and layer 5 pyrami- up” inputs are processed without filters, potentially re-
dal cells has been shown to be engaged during sensory sulting in sensory overload, thereby resulting in issues in
perception [48–50]. These dendritic spikes are often as- identifying brain states that are relevant compared to
Dendritic Dysfunction in Dev Neurosci 2021;43:201–221 203
Neurodevelopmental Disorders DOI: 10.1159/000516657NDD-associated NDD-associated
dendritic ion channels synaptic proteins
Glutamatergic Glutamatergic
Synapse Synapse
Neurexin CASPR2 Neurexin CASPR2
NMDA AMPA NMDA AMPA
mGluR mGluR
Neuroligin CaV1.x Neuroligin CaV1.x
95 SynGaP Dendritic 95 SynGaP Dendritic
D- D-
PS SHANK Spine PS SHANK Spine
NaV1.x KVx HCN CaV1.x CaV2.x CaV3.x NaV1.x KVx HCN CaV1.x CaV2.x CaV3.x
a b
“Overt” Ion channels
mRNA “Covert”
“Covert”
transcriptional
SCN2A translational regulator
GRIN2B
regulators SHANKs FMRP
GluN2B SHANKs
TBR1
CHD2 “Covert”
mRNA mGluR1
CHD8 “Overt” gene
TBR1 Neuroligin
POGZ mRNA
ANK2 SynGAP
c d
Fig. 2. Multiple high-confidence ASD/ID genes converge on neo- many “overt” NDD-genes as well as additional “covert genes,”
cortical excitatory synapses. a Several NDD-associated genes en- which play critical roles in synaptic integration and dendritic pro-
code for ion channels that are localized throughout the dendrites of cessing. d FMRP is another “covert” regulator that suppresses the
neocortical pyramidal neurons. b Similarly, NDD-associated genes translation of multiple synaptic and dendritic proteins associated
encode for a range of synaptic proteins essential for synaptic trans- with NDDs. These include various ion channels (i.e., NaV1.2 and
mission that contribute to dendritic supralinearities. c “Covert” multiple calcium channels), SHANK scaffolding proteins, SynGAP,
NDD-genes include the chromatin modifiers CHD2 and CHD8 and neuroligins, and GluRN2B. ASD, autism spectrum disorder; ID, in-
the transcription factor TBR1. They regulate the expression levels of tellectual disability; NDD, neurodevelopmental disorder.
those that instead should be ignored [54, 55]. Given the flow throughout the neocortex by functioning as coinci-
prominent role of neocortical pyramidal cells in coupling dence detectors to integrate synaptic inputs from both
associative, top-down information with local, bottom-up local and long-range projections. Importantly, abnormal
signals, instantiated through interactions between apical dendritic processing and synaptic integration within
and basal arbors, it is critical to consider whether such these neurons have been suggested to contribute to the
processes are disrupted in NDDs. social, cognitive, and communication deficits typically
characteristic of NDDs [57].
Impaired Dendritic Excitability and Synaptic The largest gene discovery effort to date identified ap-
Integration in NDDs proximately 102 genes highly associated with ASD [58].
Recent work to understand the brain regions and cell Emerging from these large-scale genetic studies are
types important for ASD has found that multiple genes “channelopathies” or dysfunction of various ion channels
converge onto pyramidal cells, with deep-layer pyramidal as causative factors in ASD pathogenesis [59–66]. A sub-
cells in prefrontal cortex of particular importance [56]. As stantial number of these genes are of the NaV, CaV, and
discussed in detail above, dendrites of deep-layer pyrami- potassium channel families, as well as HCN channels
dal neurons play a central role in facilitating information [66]. Interestingly, many of these channels are more com-
204 Dev Neurosci 2021;43:201–221 Nelson/Bender
DOI: 10.1159/000516657monly associated with dendritic function, rather than the [96, 97]. Whether this in turn affects dendritic processing
synapse proper, and are abundantly expressed in neocor- in more mature circuits has yet to be investigated.
tical pyramidal cell dendrites [67–71] (Fig. 2a). As such, SCN2A has repeatedly emerged from large-scale
pathogenic variants in genes that encode ion channels exome sequencing studies with some of the strongest as-
would likely have direct detrimental effects on dendritic sociation scores to ASD of any gene in the genome [66,
excitability. Consistent with this, both rare variants and 98–100]. SCN2A encodes NaV1.2, which exhibits unique
common polymorphisms are found within channelopa- cell type and domain-specific expression patterns
thy-associated genes, some of the most prevalent include throughout development. In the neocortex, NaV1.2 is
SCN2A, SCN1A, KCNQ3, and CACNA1E [66, 72–78]. In expressed in glutamatergic pyramidal neurons along
addition to overt effects on channel-related genes, a num- with NaV1.6, whereas NaV1.1 is the predominant sodi-
ber of high-confidence ASD genes encode proteins found um channel expressed in inhibitory interneurons [101–
directly within synapses that regulate synapse structure, 106]. Early in neocortical development, prior to 1–2
function, and connectivity, including SHANK3, SYN- years of age in humans and postnatal day 7 in mice,
GAP1, NLGN4, and GRIN2B [66]. Given their prominent NaV1.2 is the only identifiable sodium channel isoform
role in supporting synaptic activity, dysfunction in these localized to the AIS [107–109]. In mature pyramidal
genes could further impair dendritic excitability. Lastly, a neurons, NaV1.2 is replaced by NaV1.6 in the distal AIS
number of ASD gene products that include chromatin and the nodes of Ranvier [110, 111]. NaV1.6 has a lower
modifiers, transcription factors, translation regulators, voltage threshold for activation, making these sites more
scaffolding proteins, and signaling molecules may also af- susceptible to spike generation. Later in development,
fect the expression, localization, and/or trafficking of ion NaV1.2 appears to play a more dominant role in den-
channels, receptors, and other synaptic proteins [66]. dritic, rather than axonal, excitability throughout neo-
Thus, dysfunction in these genes may indirectly disrupt cortex [112]. In hippocampus, freeze-fracture immuno-
dendritic function and coincidence detection. Below, we gold labeling has revealed that NaVs are localized exclu-
discuss how multiple high-confidence ASD genes are as- sively to dendritic shafts, not spines [113]. This may also
sociated with altered dendritic structure, function, and be the case in neocortex. Human variants in SCN2A are
integration in neocortical pyramidal neurons and high- broadly categorized into different classes of NDDs as-
light impaired dendritic excitability and coincidence de- sociated with increased or decreased channel function.
tection as a central hub for ASD gene convergence. Gain-of-function variants in SCN2A that enhance
NaV1.2 activity are associated with benign infantile fa-
Sodium Channels milial seizures (BIFS) and epileptic encephalopathy (EE)
In several different neuron classes, the generation and [114–116]. By contrast, loss-of-function (LoF) variants
propagation of dendritic potentials is dependent on volt- in SCN2A are found in individuals with ASD and ID and
age-gated sodium channels [79–85]. While the impor- consist of either missense variants that dampen NaV1.2
tance of sodium channels in dendritic excitability has function or protein truncating variants that result in
been known for some time, only recently have we begun haploinsufficiency [90, 93, 117]. In neocortical layer 5
to understand the cellular and subcellular localization pyramidal neurons, heterozygous LoF in Scn2a was
patterns of different sodium channel subtypes and their shown to severely attenuate dendritic calcium transients
distinct roles in neuronal excitability. The predominant evoked by backpropagating APs (bAP) [112]. This defi-
voltage-gated sodium channel alpha subunits expressed cit was associated with a range of synaptic deficits: excit-
in the adult mammalian neocortex are SCN1A, SCN2A, atory synapses had features more commonly observed
and SCN8A, which encode NaV1.1, NaV1.2, and NaV1.6, in less mature cells, including an excess of silent syn-
respectively [86, 87]. Each of these genes is associated apses, and bAP-dependent synaptic plasticity was im-
with NDDs, including both ASD/ID and various forms of paired [112]. Furthermore, other aspects of dendritic ex-
epilepsy. Reviews of alterations in sodium channel struc- citability, including the generation of local dendritic
ture and function have highlighted how NDD-associated spikes, may be affected by Scn2a LoF. In hippocampus,
variants affect both biophysical properties as well as chan- for example, synaptic plasticity can be modulated by the
nel trafficking and modulation [88–95]. SCN3A, which generation of sodium-mediated dendritic spikes [118].
encodes NaV1.3, is expressed transiently during early de- While these effects are likely mediated by NaV1.6 in hip-
velopment, and dysfunction in this gene affects cortical pocampal neurons, NaV1.2 may be similarly critical in
folding and is associated with epileptic encephalopathy neocortical dendrites [119].
Dendritic Dysfunction in Dev Neurosci 2021;43:201–221 205
Neurodevelopmental Disorders DOI: 10.1159/000516657Loss of function of SCN8A, in contrast to SCN2A, is tions. Such hypotheses are explored in detail in a
not associated with ASD but instead with seizure-free ID companion manuscript in this issue [139].
[120, 121]. This may have to do with the different roles of
these two sodium channels. In SCN2A LoF cases, den- Calcium Channels
dritic excitability is impaired, but axonal excitability re- CaVs play fundamental roles in dendritic excitability
mains intact [112]. With SCN8A LoF, axonal excitability and synaptic integration. Activation of CaVs promotes re-
is impaired, both within pyramidal cells and also in the generative depolarizations that generate both linear and
majority of inputs to neocortex that also rely on NaV1.6 nonlinear dendritic spikes [140, 141]. AP backpropaga-
for axonal conduction [122]. Therefore, it is likely that tion into the apical dendrites of neocortical pyramidal
SCN8A LoF results in profound synaptic impairments neurons also engages CaVs, which then modulate other
that make ID diagnoses most common. ion channels and receptors, stimulate various signaling
Whether NaV1.6 loss also affects neocortical dendritic cascades, and regulate gene expression [142–144]. These
processing is less clear. Current compartmental models active dendritic processes increase the probability of AP
of Scn2a haploinsufficiency best recapitulate empirical firing, mediate dendritic neurotransmitter release, and
data when both NaV1.2 and NaV1.6 are expressed in equal regulate synaptic plasticity, such as spike timing-depen-
densities in the somatodendritic domain [112]. By exten- dent plasticity (STDP) and long-term potentiation (LTP)
sion, SCN8A heterozygosity should have similar effects as [145, 146]. Therefore, dendritic CaVs have profound ef-
SCN2A heterozygosity. While heterozygous conditions fects on synaptic integration and coincidence detection in
have not been examined, conditional knockout of Scn8a neocortical pyramidal neurons, and dysfunction of CaVs
in neocortex has been studied [123]. In these conditions, due to genetic variation would have severe effects on den-
AP-evoked dendritic calcium transients were unaffected dritic excitability and neocortical processing [147].
by NaV1.6 deletion; however, transients were imaged in Voltage-gated calcium channels are broadly classified
dendritic regions relatively proximal to the soma, a region into two groups based on electrophysiological properties:
where NaV1.2 heterozygosity also had little to no effect high voltage-activated channels consist of L-, N-, P-/Q-,
[112]. Whether more distal compartments have altered and R-type calcium channels and low-voltage-activated
electrogenesis remains unknown. Furthermore, compen- channels include T-type channels [148]. The L-type cal-
sation for NaV1.6 by NaV1.2 was evident in the AIS of cium channels are encoded by CACNA1S, CACNA1C,
these neurons. It is therefore possible that NaV1.6 loss was CACNA1D, and CACNA1F and include CaV1.1, CaVv1.2,
also compensated in dendrites [124]. CaV1.3, and CaV1.4, respectively. P/Q-, N-, and R-type
NaV1.1 (SCN1A) is the predominant sodium channel calcium channels correspond to CaV2.1, CaV2.2, and
expressed in GABAergic inhibitory interneurons [125]. CaV2.3 and are products of CACNA1A, CACNA1B, and
Variation in SCN1A is well known for its causative link to CACNA1E [148]. Last, T-type channels include CaV3.1,
Dravet’s syndrome (DS) and genetic epilepsy with febrile CaV3.2, and CaV3.3 encoded by CACNA1G, CACNA1H,
seizures plus (GEFS+) [126–128]. Haploinsufficiency of and CACNA1I [148]. Electrophysiological and immuno-
Scn1a in mice dampens interneuron excitability, result- histochemical studies have shown that all calcium chan-
ing in disinhibition of the cortical network and in turn nel subtypes are present within dendrites [149, 150].
seizures, premature death, and cognitive deficits, as ob- However, the distribution patterns of each subtype are
served in DS patients [125, 129–134]. SCN1A is also as- heterogeneous across brain regions, cell types, and even
sociated with ASD through exome sequencing and famil- different neuronal domains [151, 152]. CaV1 channels are
ial studies [66, 135, 136]; however, the mechanisms by found on the soma, proximal dendritic shafts, and within
which dysfunction of NaV1.1 contributes to ASD are not spines of hippocampal and deep-layer neocortical neu-
as well understood. Interestingly, recent work has shown rons [153, 154]. These channels are known to play an im-
that excitability deficits in parvalbumin-positive inter- portant role in triggering intracellular cascades related to
neurons resolve by postnatal day 50 in Scn1a+/− mice, synaptic plasticity [155–159]. In parallel, neocortical den-
whereas deficits in vasoactive intestinal polypeptide dritic excitability can also be supported by CaV2.x and
(VIP)-expressing interneurons persist [137]. These VIP CaV3.x channel isoforms [160–162]. CaV2.2 isoforms, in
neurons form disynaptic disinhibitory circuits with pyra- particular, appear highly expressed in layer 5 pyramidal
midal cell apical tuft dendrites through somatostatin in- dendrites [163]. Their density is highest in proximal api-
terneurons [138]. As such, the regulation of dendritic ex- cal dendrites, gradually decreasing into the distal dendrit-
citability may be indirectly affected in Scn1a+/− condi- ic arbors.
206 Dev Neurosci 2021;43:201–221 Nelson/Bender
DOI: 10.1159/000516657Dysfunction of multiple CaVs may contribute to ASD reduced HCN function [187, 188]. Thus, these channels
[164–166]; ASD gene variants are found in loci that en- can play a major role in regulating coupling between api-
code for almost all CaV alpha subunits and their associ- cal and basal compartments in neocortical dendrites.
ated beta subunit partners [167]. Somewhat confusingly, Four HCN isoforms are expressed in the brain [189].
both gain- and loss of function variants in CaVs are asso- In neocortex, HCN1 is most heavily expressed in den-
ciated with ASD. Gain-of-function (GoF) variants were drites. HCN2 is also expressed in distal apical dendrites,
found in genes that encode for CaV1 channels including but HCN3 and HCN4 are not found in neocortex [190].
CACNA1C, CACNA1D, and CACNA1F, resulting in ex- Despite the expression of both HCN1 and HCN2, to date,
cess calcium influx due to impaired voltage-dependent only variants in HCN1 have been shown to associate with
inactivation [168–171]. By contrast, loss-of-function NDDs, including epileptic encephalopathy, ASD, and ID
variants were identified in CACNA1A (CaV2.1) and CAC- [191]. Similar to SCN2A, variant genotype-phenotype
NA1H (CaV3.2), both of which reduce voltage-dependent correlations are emerging, with GoF variants more com-
activation and channel conductance [172, 173]. Thus, it monly associated with epilepsy and LoF more commonly
is likely that dendritic calcium electrogenesis is altered in associated with ASD/ID [192]. Consistent with these di-
many of these cases. Moving forward, a central question rect effects on neocortical HCN channels, similar reduc-
will be to determine how neocortical dendritic impair- tions in HCN expression are observed with other ASD-
ments contribute to ASD pathophysiology in particular associated genes, including mouse models of Fmr1 and
cases, or if CaV function in other brain regions or neuro- Shank3 [193–196].
nal compartments is more important. For example,
CaV2.1 channels, which are common to dendrites, are Potassium Channels
also critical for neurotransmitter release at presynaptic Potassium channels are ubiquitously expressed in py-
terminals across the brain [174–179]. Thus, dysfunction ramidal cell dendrites, helping to set resting membrane
in these channels may have an indirect effect on dendrit- potential and the time-course of dendritic electrogenesis
ic function, altering synaptic input to dendritic regions, [197–201]. There are conflicting reports regarding potas-
but also may have profound effects on axonal integration sium channel density in the apical dendrite relative to the
and short-term synaptic plasticity in presynaptic boutons soma, with some studies reporting low ratios [202],
[180–183]. whereas others report high ratios [203], possibly due to
differences in experimental approach. Regardless, both
Hyperpolarization-Activated Cyclic Nucleotide-Gated transient (IA) and sustained (IKD) potassium currents are
Channels observed throughout the dendrite. The precise isoforms
HCN channels are expressed broadly in neocortical that generate such currents have been difficult to dissect,
neurons. In general, HCN channels are expressed at a in large part due to significant diversity in the channel
higher density in thick-tufted pyramidal cells of the pyra- proteoforms that can produce similar currents. For ex-
midal tract compared to thin-tufted pyramidal cells that ample, IA can be produced by homotetramers of KV1.4,
project within the telencephalon [184]. Within thick- KV3.4, KV4.1, KV4.2, or KV4.3 or by heteromeric channels
tufted cells, HCN channels are expressed at increased containing a mix of these subunits [204].
density in more distal parts of the dendrite, including the While IA- and IKD-related genes have not been shown
apical dendritic tuft [185]. These nonselective cation to be associated with ASD/ID, two other potassium chan-
channels have relatively unique voltage dependence and nel genes have been identified: KCNQ3 and KCNMA1
kinetics: they are open at hyperpolarized potentials and [66]. KCNQ3 is a member of the KV7 family of potassium
close slowly with depolarization. This can create condi- channels that produces a slow outward current, with ex-
tions in which the channels contribute to resonant oscil- pression best characterized in axonal domains [205, 206]
lations in membrane potential [186]. Moreover, since and therefore likely falling outside the framework pro-
they are gated by cyclic nucleotides, HCN current ampli- posed here. KCNMA1 encodes a calcium-activated potas-
tude can be regulated by second messengers. Of note, sium current (BK) found throughout pyramidal cell ar-
HCN channels are tightly coupled to and regulated by bors, including the apical tuft, where it regulates the dura-
group 1 metabotropic glutamate receptors (mGluRs) tion of dendritic spikes [207]. Interestingly, in contrast to
present in the primary apical dendrite of deep-layer pyra- many other genes, ASD association stems exclusively
midal cells, and depolarizations mediated by group 1 from missense variants for both KCNQ3 and KCNMA1,
mGluRs in apical dendritic shafts are driven in part by with no evidence that protein truncation contributes to
Dendritic Dysfunction in Dev Neurosci 2021;43:201–221 207
Neurodevelopmental Disorders DOI: 10.1159/000516657such conditions. This contrasts markedly with cases of ep- are strongly implicated in the pathophysiology of ASD
ileptic encephalopathy where LoF stemming from protein and ID [223–225].
truncation is common, at least for KCNQ3 [208, 209]. NMDA receptors are ionotropic glutamate receptors
Such conditions mirror observations for the sodium chan- critical for fast excitatory neurotransmission and NMDA
nel SCN2A, where GoF and LoF largely associate with ep- spike initiation [226]. GRIN2B, which encodes the
ilepsy and ASD/ID, respectively. Of note, current gene GluN2B subunit of NMDA receptors, is one of the most
discovery methods for NDDs rely heavily on identifying strongly associated genes to ASD, and hundreds of vari-
protein truncations, as it is clear that such truncations im- ants in GRIN2B are found in individuals with NDDs in-
pair protein function. Missense variants, by contrast, may cluding both ASD and ID [66, 99, 227–229]. Large cohort
have little to no effect on channel function, and without studies identified numerous LoF variants in GRIN2B as
proper electrophysiological validation, it is difficult to causative for ASD and ID [230–232]. NMDA receptor
have confidence that such variants contribute to disease. subunits undergo highly regulated spatiotemporal ex-
One hint that a particular missense variant is indeed pression patterns, magnifying the detrimental effects LoF
pathogenic is recurrence. Missense variants in the same variants in GRIN2B would have on normal neurodevel-
location, identified in patients with similar conditions, opment. The GluN2B subunit is highly expressed
can increase confidence. This is the case for KCNQ3 [210], throughout the brain during prenatal development and
but fewer recurrent variants have been identified to date gradually decreases during postnatal development, be-
in other potassium channel genes. Given the opposing coming predominantly expressed in forebrain neocorti-
roles of NaV and KV channels in dendritic excitability, one cal neurons where it plays an essential role in dendritic
could envision that ASD-associated variants would result function [233]. Therefore, LoF ASD variants in GRIN2B
in GoF conditions in dendritically localized KVs (i.e., mis- would be expected to severely disrupt layer 5 pyramidal
sense variants). Potential discovery of such cases will re- neuron development and synaptogenesis. Consistent
quire far larger genetic cohorts than currently available. with this, multiple LoF variants in GRIN2B cause signifi-
cant reductions in glutamatergic transmission, with de-
Glutamate Receptors creased excitatory postsynaptic current and impaired ex-
The overwhelming majority of synaptic inputs onto citatory neuron maturation [234–237]. While human
neocortical layer 5 pyramidal neurons occur on distal variants in GRIN2B severely disrupt glutamatergic syn-
dendritic tufts, basal dendrites, and oblique dendrites of apse function, the effects of GRIN2B loss on NMDA spike
the main apical shaft, making these domains key sites for initiation and dendritic excitability have, to our knowl-
synaptic integration [211–215]. Within these regions, the edge, not been investigated in the neocortex. However,
coordinated activation of multiple glutamatergic synaps- one could easily foresee severe disruptions in dendritic
es produces a local “NMDA spike,” which is a summation excitability that may contribute to associated disorders in
of regenerative events that require AMPA and NMDA activity-dependent neuronal development.
receptor activation [216, 217]. NMDA spikes are high In addition to ionotropic glutamate receptors, changes
amplitude, long duration events (several hundred milli- in the function of group 1 mGluRs have long been associ-
seconds) capable of depolarizing the local dendritic do- ated with ASD/ID [238, 239]. The bulk of studies focused
main for sustained periods of time and are even able to on their role in synaptic transmission and regulation of
drive somatic depolarization [218]. NMDA spikes regu- plasticity [240, 241]. This in and of itself will have effects
late synaptic integration by modulating the dendritic en- on dendritic integration, but there may also be more di-
vironment to promote active synaptic input, spatiotem- rect ways in which mGluRs can regulate neocortical den-
poral information processing, and to regulate LTP and dritic excitability. These metabotropic receptors are ex-
depression – processes hypothesized to be impaired in pressed at high density in the apical dendritic shaft con-
ASD/ID [219–221]. In addition, excitable dendritic spines necting the soma with the apical tuft. In sensory cortices,
on layer 5 pyramidal neurons are necessary for regulating such mGluRs receive input from thalamus and result in
AP backpropagation, and changes in spine function and membrane depolarization that improves cooperativity
morphology significantly influence AP backpropagation between apical and basal arbors during sensory discrimi-
efficacy [222] Glutamatergic synapses and dendritic nation [242, 243]. This thalamic activation of mGluRs is
spines are major contributors to synaptic integration and hypothesized to act as a gate for sensory responses [244].
dendritic excitability of layer 5 pyramidal neurons. Con- Thus, loss of mGluR function commonly observed in
sistent with this, impairments in glutamatergic synapses ASD/ID models may interfere with this process.
208 Dev Neurosci 2021;43:201–221 Nelson/Bender
DOI: 10.1159/000516657Dendritic Scaffolding and Maintenance Proteins characteristic of ASD, including social interaction deficits The recruitment and localization of ionotropic and and repetitive behaviors [263–266], but these behaviors mGluRs is essential for normal synaptic integration. Sev- are likely attributed to multiple brain regions including eral proteins involved in AMPA and NMDA receptor (as neocortex, hippocampus, and striatum. well as ion channel) localization, spine maintenance, syn- Genetic variants in CNTNAP2 are found in individuals aptic connectivity, and plasticity are associated with ASD with ASD [267–270]. Contactin-associated protein-like 2 and ID, including NLGN1, NLGN3, CNTNAP2, SHANK3, (CASPR-2), product of the CNTNAP2 gene, is a member and SYNGAP1 (Fig. 2b) [66, 245–248]. Thus, impair- of the neurexin family. CASPR-2 is a presynaptic trans- ments in synaptic function and dendritic integration are membrane protein known to control glutamatergic syn- not limited to direct deficits of dendritic receptors and apse connectivity and spine formation, dendritic arbori- ion channels discussed above, but can also result from zation, and synaptic transmission [271]. Cntnap2 knock- dysfunction in scaffolding and maintenance proteins that out mice demonstrate malformations of neocortical keep those channels in place. As seen below, the majority development with upper layer glutamatergic neurons of work on these proteins has focused on essential syn- mislocalized into layers 5 and 6, which would be expected apse function, and to date, “downstream” effects on den- to have severe effects on integration and neocortical pro- dritic excitability have yet to be tested. This is an enticing cessing [272]. Cntnap2 knockdown in mouse prefrontal area of investigation in the future, potentially tying scaf- neocortical pyramidal neurons caused reduced excitatory fold function in the synapse to broader dendritic deficits synaptic transmission, abnormal network activity, and observed with other NDD-associated genes. synaptic dysfunction, which resulted in behavioral phe- SHANKs are a family of scaffolding proteins highly notypes similar to those found in ASD [273, 274]. Fur- enriched within the postsynaptic density (PSD) of den- thermore, Cntnap2 null mice have reduced numbers of dritic spines, with significant associations to syndromic parvalbumin-positive (PV+) interneurons and the re- and idiopathic ASD as well as ID [66, 249–253]. Here, maining PV + cells exhibited abnormal intrinsic physio- they are regarded as major organizers of excitatory syn- logical properties [275]. These findings highlight a key apse structure and function and directly interact with nu- role for CNTNAP2 in regulating synaptic communication merous proteins within the PSD, including the GluR1 between both excitatory and inhibitory neurons through- subunit of AMPA receptors, PSD-95-associated proteins, out the neocortex. Homer, and other SHANK family members [253]. As SYNGAP1 is a significant risk gene for ID, ASD, and seen with other cytoskeletal proteins important for spine epileptic encephalopathy [66, 232, 276–278]. Heterozy- formation and maintenance, genetic deletion of SHANK gous, de novo LoF variants in SYNGAP1 are causative in proteins reduces the levels of AMPA and NMDA recep- approximately 1% of individuals with ID and develop- tors [254]. This, in turn, results in significant morpho- mental delay, demonstrating its essential role in brain de- logical and functional deficits as well as reductions in velopment and function [279, 280]. SYNGAP1 encodes spine density in neocortical neurons of SHANK-deficient the synaptic Ras GTPase-activating protein (SynGAP), mice [255–257]. In addition, ASD variants in SHANK3 which is highly enriched in the PSD of mature neocortical result in reduced mGluR group 1 receptor expression and and hippocampal pyramidal neurons [281]. SynGAP disrupt mGluR-dependent synaptic plasticity [258]. negatively activates the small GTP-ases Ras- and Rap- ASD-associated variants are found within NLGN1, GAP to promote AMPA receptor trafficking, membrane NLGN3, and NLGN4, which encode NLGN1, NLGN3, incorporation, and synaptic LTP and depression (LTD) and NLGN4 members of the neuroligin family of cell ad- [282, 283]. In addition to its role in synaptic plasticity, hesion molecules [259]. Neuroligins are localized within SynGAP is fundamental for dendritic spine maturation. postsynaptic domains of dendritic spines and form trans- In neocortical neurons, SynGAP expression levels rise membrane connections with presynaptic neurexin pro- dramatically during postnatal development, around post- teins that promote synapse development, function, and natal day 14 in mice [284]. Normal SynGAP function is maintenance [260]. In addition, neuroligins interact with critical during this developmental window as haploinsuf- PSD-95, SHANKs, and AMPA and NMDA receptors ficient Syngap1 mice display aberrant dendritic spine within spines to regulate excitatory synaptic formation maturation; however, knockout of Syngap1 late in devel- and transmission in hippocampal neurons [261, 262]. opment had no significant effect on synaptic function Mouse models of Nlgn1 and Nlgn3 knockout as well as [285, 286]. Therefore, human variants that disrupt Syn- LoF missense variants display behavioral phenotypes GAP function during critical periods of synaptogenesis Dendritic Dysfunction in Dev Neurosci 2021;43:201–221 209 Neurodevelopmental Disorders DOI: 10.1159/000516657
would be expected to have permanent effects on excit- GABRB1, and GABRG1 in 4 siblings with ASD [303]. A
atory integration and synaptic plasticity in developed similar duplication of this GABA receptor gene cluster
neurons. However, a recent study by Creson et al. dem- has been reported in other individuals with ASD who
onstrated that re-expression of SynGAP in adult Syngap1 present with a range of behavioral phenotypes [304–307].
heterozygous mice restored neuronal excitability deficits, Consistent with genetic studies, multiple GABA receptor
memory impairments, and seizure thresholds [Creson subunits were found at significantly lower expression lev-
Colgin, 2019, DOI: 10.7554/eLife.46752]. These findings els in postmortem brain of ASD individuals as compared
offer insight on the development of new treatment strate- to neurotypical controls [308, 309]. While GABAergic in-
gies that rescue expression or function of SynGAP to treat terneurons and multiple GABA receptor subunits are in-
SYNGAP-associated NDDs in adult patients. volved in ASD pathophysiology, it will be important for
future work to determine how GABAergic circuitry func-
Gamma-Aminobutyric Acid Receptors tions in tandem with glutamatergic receptors to control
Gamma-aminobutyric acid (GABA) is the primary in- dendritic excitability and integration and how this is al-
hibitory neurotransmitter in the adult mammalian brain. tered in ASD. In addition, pathogenic variants in several
Dysfunction of inhibitory microcircuits within the neo- ASD-associated genes mentioned throughout this re-
cortex has been linked to ASD and other NDDs through view, such as CNTNAP2, TBR1, and PTEN, result in both
a variety of mechanisms including abnormal develop- glutamatergic and GABergic deficits, which could further
ment, migration, intrinsic properties, or connectivity potentiate impairments in dendritic processing. Taken
[275, 287, 288]. Different subtypes of GABAergic inter- together, these findings suggest that although the etiology
neurons synapse onto discrete domains of excitatory neu- of ASD is heterogenous, excitatory synapse dysfunction
rons, including layer 5 pyramidal neurons in the mPFC, and impaired neocortical dendritic processing may be
where they play unique roles in modulating pyramidal one core feature among some individuals with ASD and
cell excitability and plasticity. PV-positive interneurons ID.
target the somatodendritic domain and AIS of pyramidal
neurons, whereas SOM cells primarily synapse onto the “Covert” Mechanisms in ASD/ID That Regulate
dendrites [289–291]. Martinotti SOM+ interneurons Dendritic Impairments
synapse onto distal apical dendrites of layer 5 pyramidal Efforts to identify convergence between ASD genes
neurons, where they tightly control dendritic activity have broadly separated high-confidence ASD genes into
[292]. Specifically, they inhibit pyramidal cell firing dur- two main groups: synaptic function and transcriptional
ing sustained periods of high activity and are also capable regulation. However, evidence suggests that these two
of effectively blocking the generation of dendritic spikes groups intersect at multiple levels, perhaps leading to dys-
[293]. Last, VIP interneurons are found in layer 2/3 and function of shared downstream processes [310–312]. In
preferentially target other neocortical interneurons in- support of this, recent work by Jing et al. used Perturb-
cluding PV and SOM neurons in layer 5 [294–296]. Seq, a novel high-throughput genetic screen that allows
Therefore, pathogenic variants in genes involved in GA- for single-cell resolution of phenotypic changes caused
BAergic interneuron subtype function or in genes that by introducing an array of genetic perturbations. This
encode GABA receptor subunits could potentially impair technique allows for the identification of points of con-
neocortical neuron dendritic processing. Several genes vergence between multiple seemingly diverse ASD/NDDs
that encode GABA receptors have been implicated in in unique cell types and transcriptomic networks across
NDDs, including ASD [297–300]. Whole-exome se- the developing brain [313]. Here, we have discussed how
quencing studies revealed GABRB2 and GABRB3, which dysfunction of multiple NDD-associated genes that en-
code for the GABAA receptor beta-2 and beta-3 subunits, code for various subtypes of ion channels, receptors, and
are among the top 102 high-confidence ASD genes [66]. scaffolding proteins impairs dendritic excitability and
Familial studies identified single nucleotide polymor- synaptic integration in neocortical pyramidal neurons.
phisms within genes that encode additional GABA recep- We term these particular genes “overt” genes, as loss or
tor subunits including GABRA4 (alpha-4), GABRB1 dysfunction of their protein products directly results in
(beta-1), and GABRB3 (beta-3) in patients with ASD neocortical dendritic deficits. By contrast, an additional
[301, 302]. In addition, a recent study found a 2.4 Mb du- pool of NDD-associated genes that encode chromatin
plication of 4p12 to 4p11 that consists of GABA receptor modifiers, transcriptional and translational regulators,
subunit gene clusters that include GABRA4, GABRA2, and trafficking proteins may function in a more “covert”
210 Dev Neurosci 2021;43:201–221 Nelson/Bender
DOI: 10.1159/000516657way to also affect dendritic integration, in part through CHD8 could impair dendritic excitability and integration
their regulation of “overt” mechanisms discussed above. by affecting target genes involved in transcription, den-
Below, we highlight emerging evidence of such interac- dritic scaffolding, and excitability. Consistent with this,
tions in select NDD-associated genes. Chd8 knockdown in mice causes delayed neocortical
Fragile X syndrome is the single most common form neuron migration and reduced dendritic outgrowth
of inherited ID and monogenic cause of ASD [314]. Frag- [324].
ile X syndrome is caused by the expansion of a CGG re- TBR1 is another ASD-associated transcriptional regu-
peat in the 5′ UTR region of FMR1, which results in the lator gene that controls the expression of several other
loss of FMR1 and, in turn, its protein product FMRP genes involved in the etiology of ASD [325]. Tbr1 controls
(fragile X mental retardation protein) (Fig. 2d) [315]. the transcription of Grin2b, Scn2a, and Ank2 genes in-
FMRP is an RNA-binding protein that suppresses the volved in excitatory synaptic function, dendritic excit-
translation of numerous mRNA targets including multi- ability, and protein localization in axonal structures, re-
ple Shanks, Scn2a, multiple calcium channel genes, Syn- spectively [326]. TBR1, a T-box transcription factor, is
gap1, Nlgns, and Grin2b, which are essential for normal regarded as a master regulator of cortical development as
dendritic excitability [316, 317]. FMRP shuttles mRNA it plays a fundamental role in the differentiation and iden-
from the nucleus throughout the cytoplasm, but it is also tity of deep-layer neocortical pyramidal neurons [327–
highly enriched within dendritic spines, where it colocal- 329]. Tbr1 mutant mice have fewer excitatory and inhib-
izes with many of its mRNA targets [315]. The loss of itory synapses onto neocortical dendrites that are partial-
FMRP would therefore likely lead to aberrant expression ly due to reduced WNT signaling [330, 331]. Both
of multiple proteins involved in dendritic morphology excitatory and inhibitory synaptic deficits can be rescued
and integration. Consistent with this, neocortical neu- with WNT agonists [332]. Interestingly, Tbr1 heterozy-
rons of individuals with Fragile X syndrome, including gosity in layer 6 pyramidal neurons converts their den-
layer 5 neurons, have abnormally long, immature spines dritic arborization into layer 5-like apical dendrites,
[318]. In addition, the activation of mGluRs upregulates where ectopic growth of the apical dendrite extends into
FMRP expression within spines. This demonstrates a layer 1 instead of their typical termination with little ar-
functional link between mGluR stimulation and local borization in layer 4 [333]. How these ectopic dendritic
translation in spines, a process necessary for excitatory tufts impact the function of affected neocortical areas re-
synapse function, morphology, and plasticity [319, 320]. mains unclear. Interestingly, these conditions may serve
The reciprocal relationship also exists as FMRP controls as an excellent model in which to test the relative function
the translation of mGluR, and the loss of FMRP causes of different deep-layer pyramidal cells, as this would cre-
increased mGluR signaling, a process known as the ate situations where layer 6 neurons may have typical bas-
mGluR hypothesis of fragile X syndrome [321]. Ultimate- al inputs but vastly different apical inputs. One major
ly, the dendritic phenotypes observed in the Fragile X question would be to test whether such neurons now
syndrome patients and animal models of FMR1 loss over- adopt processing features more commonly associated
lap with animal models of haploinsufficiency of multiple with layer 5 cells, rather than those ascribed to layer 6
FMRP mRNA targets (i.e., Scn2a+/−and Syngap1+/− mice), (e.g., gain control of cortical columns) [334].
further highlighting impaired neocortical dendrites as a PTEN encodes the protein PTEN, a phosphatase
point of convergence between genes with the strongest strongly associated with ASD and ID [335, 336]. PTEN is
association scores. highly expressed in both glutamatergic and GABAergic
In addition to genes that regulate translation, damag- neurons, where it acts as an inhibitor of PI3K/AKT sig-
ing variants in genes that control transcription can also naling through the activation of receptor tyrosine kinases
affect genes directly involved in dendritic excitability (RTKs) [337–339]. Conditional knockout of Pten in neo-
(Fig. 2c). The chromatin modifiers, CHD2 and CHD8, cortical glutamatergic pyramidal neurons results in aber-
each carrying strong ASD association, are both expressed rant dendritic and axonal arborization and somatic over-
in human deep-layer neocortical neurons, where they growth, due to heightened β-catenin expression, causing
regulate the expression of several other genes involved in macrocephaly and deficits in social behaviors [340–342].
brain development [56, 66, 322]. Further, CHD8 and Homozygous loss of Pten weakened excitatory synaptic
CHD2 targets include numerous ASD-linked genes, in- transmission and plasticity in hippocampal neurons
cluding SCN2A, GRIN2B, SHANK2, POGZ, TBR1, and [342]. The effects of Pten loss on dendritic excitability in
ANK2 [323]. Therefore, haploinsufficiency of CHD2 and neocortical neurons remain unclear [342–344]. In addi-
Dendritic Dysfunction in Dev Neurosci 2021;43:201–221 211
Neurodevelopmental Disorders DOI: 10.1159/000516657tion, PTEN loss in mouse cortical GABAergic interneu- Moving forward, several areas of investigation will be
rons results in reduced somatostatin cell number shifting critical to better understand how dendrites are affected in
the ratio of PV/somatostatin interneurons, which, in ASD/ID. First, more complete genotype-phenotype cor-
turn, may lead to abnormal dendritic function and inte- relations of genes known to regulate dendritic function
gration [345]. will help to better identify the precise conditions in which
Here, we have discussed only a few “covert” genes that aspects of dendritic integration are affected. For example,
have been shown to directly regulate the expression or in both SCN2A and GRIN2B, a large number of missense
localization of “overt” genes in dendrites of neocortical variants can be associated with a range of disorders, like-
pyramidal neurons. This is likely the tip of an iceberg that ly due to differential effects in channel biophysics, ligand
will be better revealed as deep genetic phenotyping of affinity, trafficking, etc. While a great deal can be done in
multiple ASD-associated models emerges in the coming heterologous expression systems, it can often be difficult
years. Loss-of-function of these “covert” genes results in to understand the end effects of such variation in non-
functional, morphological, and organizational deficits on native systems. Second, deep phenotyping of the neuro-
neocortical neurons, particularly in layer 5. Of note, many nal proteome, perhaps focusing on “overt” dendritic ex-
of these transcriptional regulators modify expression lev- citability genes, in animal models with “covert” gene dys-
els of multiple “overt” genes at once, making predictions ruption may help us to better understand how chromatin
about the final effects on synaptic and dendritic function modification and other forms of gene regulation affect
difficult without empirical tests. the dendrite. Last, the development of ASD/ID-relevant
behavioral approaches that are amenable to simultaneous
imaging, recording, and ideally, manipulation of dendrit-
Conclusion and Future Directions ic activity in ASD/ID-relevant models will not only be key
to understanding the role of dendrites in NDDs, and also
As mentioned at the outset, this review focused pri- may shed light on components of dendritic function nec-
marily on the role of dendritic integration in neocortical essary for neurotypical processing.
areas for several reasons. First, our understanding of neo-
cortical dendritic function is relatively refined both in
terms of cellular mechanisms andin vivo function, with Acknowledgments
clear models emerging for the role of dendritic integra-
We are grateful to members of the Bender Lab, including Anna
tion in conscious perception and decision-making. Sec-
Lipkin and Selin Schamiloglu, as well as Matthew McGregor, Dr.
ond, neocortical pyramidal cells appear to be a point of Guy Bouvier, Dr. Stephan Sanders, and Dr. John Rubenstein for
convergence for several ASD/ID-associated genes acting discussions and comments on this review. This work was support-
both overtly and perhaps covertly to affect dendritic inte- ed by the Simons Foundation Autism Research Initiative (513133,
gration. As highlighted recently for the function of psy- 629287) and the NIH (MH112729 and MH125978).
chedelics [346], our hope is that future studies take den-
dritic excitability into consideration in parallel with key
experiments examining molecular, cellular, systems, and Conflict of Interest Statement
behavioral consequences of ASD/ID-associated variation The authors have no conflicts of interest to disclose.
in such genes.
ASD and ID are brain-wide disorders, and while neo-
cortex is thought to be important for ASD/ID etiology, it Author Contributions
is not affected in isolation. A wealth of studies have high-
lighted the importance of other key circuits, including A.D.N. and K.J.B. contributed equally to this work.
basal ganglia, amygdala, hippocampus, and cerebellum
[87, 347–365]. Importantly, many of the concepts dis-
cussed above, including the mechanisms supporting den-
dritic nonlinearities, are relevant across these structures.
Thus, while we highlight neocortex here, these themes
likely extend to other structures, each with their own rules
governing how dendritic excitability shapes the process-
ing of relevant information.
212 Dev Neurosci 2021;43:201–221 Nelson/Bender
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